Boron compounds aldol reactions

The aldol reaction is a versatile method for the construction of new carbon-carbon bonds in a regio-, diastereo-, and enantioselective manner. During the last two decades, major progress toward the total synthesis of macrolide antibiotics was made as a result of the development of the stereoselective aldol reaction in acyclic systems. This section is concerned mainly with the boron-mediated aldol reaction, which is particularly effective for the efficient synthesis of P-hydroxy carbonyl compounds [2]. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Chiral boron Lewis-acid complexes have been successfully used in Diels-Alder and aldol reactions. Representative chiral Lewis-acidic boron compounds are shown in Figure 2.297-301... 

Boron enolates are often used for aldol reactions. Boron enolates are usually prepared from the corresponding carbonyl compounds, tertiary amine, and a boron source (e.g., dibutylboron triflates). The aldol reactions proceed via a six-membered transition state to give high diastereo-selectivity which depends upon the geometry of the boron enolates. 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

Treating boron reagent 45a with an oxazoline compound gives the azaeno-late 52. Subsequent aldol reaction of 52 with aldehyde yields mainly threo-product (anti-53) with good selectivities (Scheme 3-18).38... 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Dialkylboron trifluoromethanesulfonates (triflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazolidinones.4 Recently, the combination of dicylohexylboron trifluoromethanesulfonate and triethylamine was found to effect the enolization of carboxylic esters.5 The boron-mediated asymmetric aldol reaction of carboxylic esters is particularly useful for the construction of anti (3-hydroxy-a-methyl carbonyl units.6 The present procedure is a slight modification of that reported by Brown, et al.2... 

Even greater diastereoselectivity in die aldol reaction can be achieved using boron etiolates as the carbon nucleophile. Boron etiolates are easily prepared from aldehydes and ketones, and the syn and die anti isomers can be separated as pure compounds. They react with aldehydes and ketones to give aldol products by a similar transition state. The difference is fliat boron oxygen bonds are shorter than lidiium oxygen bonds, and thus steric interactions in the transition state are magnified and result in greater diastereoselectivity. 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Sllyl enol ethers react with aldehydes at -78°C, and with ketones near 0°C. Note that the aldol reaction of sllyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K0ster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9... 

The isolation of the initial aldol products from the condensation of the enolates of carbene complexes and carbonyl compounds is possible if the carbonyl compound is pretreated with a Lewis acid. As indicated in equation (9), the scope of the aldol reaction can also be extended to ketones and enolizable aldehydes by this procedure. The condensations with ketones were most successful when boron trifluoride etherate was employed, and for aldehydes, the Lewis acid of choice is titanium tetrachloride. The carbonyl compound is pretreated with a stoichiometric amount of the Lewis acid and to this is added a solution of the anion generated from the caibene complex. An excess of the carbonyl-Lewis acid complex (2-10 equiv.) is employed however, above 2 equiv. only small improvements in the overall yield are realized. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

Several other chiral boron reagents are available for asymmetric aldol reactions however, each of these compounds must be synthesized in the laboratory. In certain situations, some will give higher stereocontrol than the Ipc ligands, and hence for a given reaction their application could be pursued. Chiral reagents 53 and 54 have been used in the synthesis of bryostatin 7 [36] and the Taxol side-chain [37], respectively, while bis-sulfonamide 55 has been used in the synthesis of a C24-C35 segment of FK-506 (Scheme 9-18) [38]. 

In the first total synthesis of bafilomycin A by Evans and Calter [16], the syn aldol reaction between ketone 29 and aldehyde 176 was a pivotal transformation (Scheme 9-51). Using a (Z)-enolate, it could be expected that aldehyde 176 would have a small bias for the desired ann-Felkin adduct, however, control from the ketone component would be needed for high stereoselectivity. Use of common metal enolates led to poor stereocontrol however, model studies indicated that the (Z)-chlorophenyl boron enolate, in conjunction with cyclic protection of the C21-C23 diol, induced high selectivity in the desired sense. In practice, the coupling of the required aldehyde 176 and enolate 77 afforded 178 with >95%ds. Compound 178 was then successfully elaborated to give bafilomycin A]. In the second reported synthesis of bafilomycin A, Toshima et al. carried out the same aldol coupling to form the Cn-Cig bond [68]. 

Alkenylaminoboranes (14), though not in the category of alkenyloxyboranes, also undergo aldol reactions with carbonyl compounds (Scheme 13). Pure alkenylaminoboranes can be isolated from the reaction of a ketimine, boron trichloride and triethylamine in dichloromethane. ... 

---